Cancers as malignant tumor hold the first place of the cause of death in Japanese, and there has been no decisive therapeutic method for completely curing the cancer. Novel therapeutic methods specifically targeting the cancer have been expected not only from the view point of high therapeutic effects but also from the view point of alleviating side effects. Therefore, developments of gene therapy aiming to specifically target the cancer have been particularly desired. While there are various methods for targeting the cancer and tumor, there are many cases where molecules that are highly expressed only in cancer and tumor cells are utilized by some means. Such tumor specific molecules that are specifically expressed in cancer cells such as tumor markers have been reported. Ideal molecules for this purpose are such molecules as are expressed in the cancer cell as strongly as possible and as are scarcely expressed in normal cells.
Most of the vectors for introducing genes used in the gene therapy of the cancer today are non-proliferative vectors that are genetically modified so that viruses are not proliferated only by introducing the therapeutic vectors after virus infection for securing safety. However, there is a problem that it is natural that the gene cannot be introduced to sections which a virus solution cannot reach by some physical reasons so long as the vector is a non-proliferative type in the case where the vector is administered in vivo in actual clinical treatments, even when the vector itself has an ability for exhibiting a high gene-introducing efficiency. When gene therapy is applied to the cancer using the non-proliferative vector, it is impossible to introduce the genes in all the cancer cells in the body, even though vectors having so excellent gene-introducing efficiency are used in in-vitro experiments.
In other words, the currently used gene therapy using the non-proliferative vector involves such a large restriction that another therapeutic gene that can give some effect to the cells in which the gene is not introduced must be used. However, even in such a case it is impossible to kill all the cancer cells, or only the cancer cells, so that the therapeutic effect of the gene therapy is quite restricted. Accordingly, a perfect cure of the cancer by gene therapy is difficult to attain unless a quite large problem that the cancer recurs from the cancer cells in which the genes are not introduced is not conquered.
Accordingly, virus vectors that proliferate only in the cancer are reported as the vectors for conquering the above-mentioned problem. In a method, a virus gene necessary for proliferation of a virus vector has been attempted to be expressed with a promoter of a cancer specific molecule in order to control the vector so that the virus proliferates in the cancer cell and does not proliferate in normal cells (Rodruguez, R., et. Cancer Res, 57, 2559-2563, 1997). However, specificity for targeting only the cancer as well as the promoter activity was insufficient yet, and developments of the proliferative vectors that are decisively effective have not been successful yet.
Under these situations, survivin was reported as one of novel proteins as a member of inhibitors of apoptosis (lAP) gene family. Survivin is greatly characterized in cancer-specific expression with no expression in differentiated normal tissues (Ambrosini, G. et al., Nat. Med. 3, 917-921, 1997). Expression of survivin is the largest at G2/M stage as a mitotic stage of the cell, and is suppressed in the cell in a non-mitotic resting stage (Li, F, et al.; Nature, 396, 580-584, 1998). A survivin promoter that regulates expression of the survivin gene has an activity for cancer-specific expression (Bao, R. et al.; J. Natl. Cancer Inst. 194, 522-528, 2002), and is considered to have substantially no expression activity of almost all the genes in the normal cell. Accordingly, while it is expected that pharmaceutical compositions for targeting and killing the cancer cells can be developed by cancer cell-specific expression of various genes for cancer therapy, pharmaceutical compositions having as an effective ingredient the proliferative vector containing the survivin promoter have not been proposed yet.